Fat as a metabolic fuel = P & E notes Flashcards
State advanatges of using fat as a metabolic fuel
. Energy to mass ratio - double the energy per gram dry weight than glycogen
. Low hydration levels due to hydrophobic nature - low mass.
Energy dense and inert
Use as an energy source does not interfere with body function- unlike the use of protein supplies which involve muscle breakdown
Can be readily mobilised
Ideal energy source for tissues with high energy demand
Fatty acids are more reduced than glucose
There are large stores of fat in the human body
State some disadvantages of using fat as a metabolic fuel
. Slow energy release - large number of metabolic processes before it can enter the TCA cycle
. Cannot be transported across cell membranes - so requires intracellular lipases to mobilise TAGs as fatty acids -
Cannot be transported directly across cell membranes but instead requires lipases to mobilise TAGs as fatty acids and an extracellular lipase is needed to take up circulating TAGs as fatty acids
Insoluble in water so need specialised transport systems
Outline process of lipolysis
TAG to DAG + FA - ATGL
DAG to MAG + FA - HSL
MAG to glycerol + FA - MAG lipase
Enzymes HSL = Horomone Sensitive Lipase, MAG lipase = Monoacylglycerol lipase, ATGL = Adipose Triacylglycerol lipase
Substances - TAG = triacylglycerol
DAG = diacylglycerol
MAG= monoacylglycerol
FA = fatty acid
Role of albumin
- Fatty acids are transported in blood by being bund to albumin
Hormonal regulation of lipolysis
Adrenaline = … lipolysis
Insulin = …. lipolysis
stimulates
inhibits
Lipid droplets are covered with ….
significance of this …
Perilipin = a protein which covers lipid droplets
Perilipin = controls adipocyte lipid metabolism - How ?
Perilipin = bound to an ATGL activator called CGI 58
How does adrenaline stimulate lipolysis
Adrenaline = binds to GPCRs
. Adenylate cyclase converts ATP to cAMP which activates PKA
- Phosphorylates HSL & perilipin
. ATGL is activated because phosphorylation of perilipin causes CGI 58 to be dissociated from perilipin
How does insulin inhibit lipolysis
Insulin stimulates phosphodiesterase because:
Insulin - stimultates phosphodiesterase which converts cAMP to ATP so activation of PKA is prevented
. Insulin = prevents activation of PKA - thus inhibiting lipolysis
State the enzyme which catalyses the production of fatty acyl-CoA
Fatty acid = esterified with CoA by acyl-CoA synthetase
Outline Carnitine Shuttle
Reason for Carnitine Shuttle = Fatty acyl CoA cannot cross the IMM
IMM = Inner Mitochondrial Membrane
CAT1 = Catnitine acyl transferase
CAT1 exchanges CoA for carnitine
Translocase shuttles fatty-acyl carnitine across the IMM in exchange for carnitine
CAT 2 = exchanges carnitine for CoA
Elaborate on the control of carnitine shuttle
Control of carnitine shuttle is by regulation of CAT1 bymalonyl-CoA(unique intermediate in synthesis of FAs) whichinhibits CAT1
Produced from acetyl-coA by acetyl-coA carboxylase (ACC)
ACC mediated by whole body energy status
ACC activated byinsulin- synthesis
ACC inhibited byglucagon- oxidation
Fed state (after a meal) -> more insulin -> activation of ACC -> increased synthesis of FAs + decreased oxidation
ACC mediated by cellular energy status
ACC activated byATP- synthesis
ACC inhibited byAMP- oxidation
AMP dependent protein kinase inhibits ACC
Where does B oxidation take place
In the mitochondrial matrix
How do fatty acids enter the cytoplasm of hepatocytes
FA - enter the cytoplasm of hepatocytes either through simple diffusion or facilitated diffusion through FAT
FAT = fatty acid translocase
CAT-1 = rate limiting enzyme of beta oxidation
Diseases - involving CAT enzymes & Carnitine
Clinical relevance - carnitine deficiency
Lack of CATs
Muscle weakness + fatigue in prolonged exercise
Treatment = carnitine supplements
Experimental Evidence
Experimental evidence
Malonyl Co-A inhibits oxidation of fatty acids to ketone bodies in homogenates (whole cell fragments) but not in mitochondrial fragments
Inhibits entry to the mitochondria
Malonyl CoA = inhibits Carnitine Acyl Transferase -1
Where does B- oxidation take place
State the products of B oxidation
Location = mitochondrial matrix
Overall pathway = produces
acetyl-CoA - used in TCA
NADH & FADH - used in ETC
One B oxidation = shortens the fatty acyl-CoA chain by ……
2 carbon atoms
State the reactions of B oxidation
Reactions of β oxidation
FAD-dependent oxidation
Hydration
NAD+-dependent oxidation
Thiolysis
State in detail the steps in Beta oxidation
Oxidation
Fatty Acyl CoA -> Trans Enoyl CoA &
FAD -> FADH2
Enzyme: Acyl CoA Dehydrogenase
Hydration
Trans Enoyl CoA + H20 -> Hydroxyacyl CoA
Enzyme: Enoyl CoA Hydratase
Oxidation
Hydroxyacyl CoA + NAD -> NADH + H+ + Ketoacyl CoA
Enzyme: Hydroxyacyl CoA Dehydrogenase
Thiolysis
Ketoacyl CoA + CoASH -> Fatty Acyl CoA (2 C shorther) + Acetyl CoA
Acetyl CoA = Krebs /TCA cycle
Fatty Acyl CoA = enters B oxidation cycle again
Name 3 defects of fatty acid oxidation
MCAD deficiency
Carnitine deficiency
Jamaican vomiting sickness
MCAD deficiency elaborate
MCAD deficiency means that medium chain length fatty acids build up as intermediates of beta-oxidation
They bind to carnitine to form carnitine conjugates which are then excreted in the urine resulting in carnitine deficiency
Rare genetic disorder
Onset in infancy with 25% sudden and unexpected death
50% have hypoglycaemia because cannot rely as much on fat stores for ATP synthesis
No or reduced ketogenesis on fasting
Symptoms are vomiting, lethargy, seizures, coma, death
Carnitine deficiency
A relatively rare genetic disorder, 1/19000
Cardiomyopathy because the heart is very dependent on fatty acids
Fatty infiltration of organs because they are not completely oxidised by other organs
Muscle weakness because slow twitch fibres are heavily reliant on fatty acids as fuel
Hypoglycaemia as glucose stores are used in place of fats
Jamaican vomiting sickness
Not a genetic defect, but a poisoning which inhibits an enzyme
Unripe fruit from the ackee tree contains a compound called hypoglycin A
When metabolised, this compound inhibits acyl-CoA dehydrogenase
This prevents beta-oxidation so the body has to rely solely on glucose
Leads to hypoglycaemia, coma and death
Cytoplasmic fatty acids binding protein (cFABP) moves fatty acids to intracellular compartments as fatty acids are insoluble in the cytoplasm so have to bind to a soluble protein, this includes their transport to the mitochondrial membrane to move into the mitochondria for beta-oxidation
The enzymes of fatty acid oxidation
The acyl-CoA dehydrogenase is different depending on the length of the fatty acid chain
VLCAD- very long chain acyl-CoA dehydrogenase is 18+ carbons
LCAD- long chain acyl-CoA dehydrogenase is 12-18 carbons
MCAD- medium chain acyl-CoA dehydrogenase is 6-12 carbons
SCAD- short chain acyl-CoA dehydrogenase is 4-6 carbons
Unsaturated fatty acids
Contain a cis double bond which is converted to a trans bond by isomerase
Reductase then removes the double bond and makes the fatty acid a substrate for ongoing oxidation
Very long chain fatty acids
Have 20-22 carbons so must first be shortened in the peroxisomes to 16-18 carbons (called peroxisomal beta-oxidation), then transferred to mitochondria for beta-oxidation
Peroxisomal beta-oxidation does not generate ATP, but instead hydrogen peroxide
Odd chain length fatty acids
Beta-oxidation generates acetyl-CoA which has 2 carbons, but with odd chain length fatty acids, the last round of beta oxidation won’t do this so the last round will start with 5 carbons
The last cycle will generate 1 acetyl-CoA and 1 propionyl-CoA (3C) which can be metabolised to succinyl-CoA to enter the TCA cycle
Branched-chain fatty acids
Start in the peroxisomes for alpha-oxidation, before they are transferred to the mitochondria for beta-oxidation
Name the shuttle in
- fatty acid synthesis
- fatty acid oxidation
FA synthesis = CITRATE shuttle
FA oxidation = CARNITINE SHUTTLE
Fat Facts
Fats give twice as much energy per gram when oxidised than glucose
Weighs less than glycogen because it is an anhydrous store because it is hydrophobic
6 times more efficient to store than glycogen
Assimilation of dietary fats
Outline & Read about the process of
Assimilation, emulsification, absorption, packaging as chylomicrons
The large triglyceride droplet in the intestinal lumen is hydrophobic and inaccessible to pancreatic lipases
Bile salts are powerful detergents which breakdown the large lipid droplets into smaller droplets
Pancreatic lipases can now attack the droplets- they require a large surface area to operate
Lipases then breakdown TAGs into NEFAs and glycerol which spontaneously arrange into mixed micelles with a hydrophobic centre and a hydrophilic surface- these can be absorbed through the intestine wall
Triacylglycerols are enclosed in lipoprotein to form chylomicrons which consist of a phospholipid monolayer with apolipoproteins embedded which act as cofactors for enzymes and ligands for receptors
Chylomicrons are then released into the lymphatic system through exocytosis
Transport and release of fatty acids
Chylomicrons travel in the lymphatic system because they are too big to enter capillaries
Lymphatic vessels drain into large veins so lipids bypass the liver
Lipoprotein lipase on the surface of endothelial cells break down chylomicrons- these are found on the surface of adipose and muscle tissue and releases NEFAs which are then taken up by the cells
The role of insulin in fat distribution and storage
Insulin causes the body to build-up TAG stores as it causes GLUT4 recruitment which increases adipocyte intracellular glucose which can be stored as TAGs
Insulin is antilipolytic so prevents breakdown of fat stores and stimulates production of lipoprotein lipase to allow the breakdown of chylomicrons so the NEFAs can be stored
Insulin stimulates transcription of genes involved in fatty acid esterification
